PURPOSE: The purpose of this study is to determine in subjects with type 1 diabetes mellitus: whether glycemic control can be achieved at least as effectively with an insulin regimen involving pre-meal inhaled insulin plus a single bedtime Ultralente injection as with a conventional subcutaneous insulin regimen involving 2-3 injections per day; and the toleration and safety of inhaled insulin therapy and its effect(s), if any, on measures of pulmonary function. METHODS: This is an open-label, 3-month, parallel, multicenter study. A total of 60 subjects ( a total for all sites) with type 1 diabetes will be evaluated in this study. Subjects who successfully complete the 3-month comparative trial will be eligible to receive inhaled insulin in an open-label protocol which has been extended for two consecutive years. In the comparative trial the control condition is insulin injection therapy, given either BID or TID, depending upon the subject's usual (prestudy) administration regimen. The study condition is tid AC dosing of inhaled human insulin plus a single bedtime Ultralente injection. For subjects randomized to both groups, insulin doses will be adjusted to optimize control based on glucose monitoring results. In the extension study, patients may elect to return to subcutaneous insulin or to continue or start inhaled insulin. As in the 3-month trial, insulin adjustments will be based on glucose monitoring results. Safety parameters include pulmonary function testing performed every three months, as well as yearly EKG and chest X-ray. Clinic visits will occur every 4 weeks so that both the safety and efficacy of trial may be monitored. RESULTS AND CONCLUSIONS: Results from the initial 3-month study indicate that inhaled insulin is well- tolerated and glycemic control is comparable to insulin administered subcutaneously. The results of the 3-month study were presented in abstract form at the 58th Scientific Sessions of the American Diabetes Association, June. At the present time, subjects are continuing to be followed in the 2nd one-year extension of the study, and the study sponsor plans to continue extending the study until the FDA approval is obtained. SIGNIFICANCE: Recently, the long-term benefit of tight glycemic control with aggressive insulin therapy has been demonstrated in patients with diabetes in the Diabetes Control and Complications Trial (DCCT). Results from the DCCT showed a significant reduction in diabetic complications in insulin-dependent subjects using an intensified insulin regimen. However, despite studies showing the benefit of this type of therapy, aggressive insulin therapy has been slow to gain acceptance in clinical practice settings. The poor patient acceptance is due to inconvenience of the therapy as well as the unpredictability of insulin action post-prandially. Therefore, an inhaled insulin which is easy to administer and provides a predictable pattern of insulin action may be more acceptable to patients requiring insulin therapy and may provide better overall glycemic control. FUTURE PLANS: Plans for phase III studies are underway by the study sponsor, Pfizer, Inc.